PXD014017

PXD014017 is an original dataset announced via ProteomeXchange.

Title	Immunopeptidomics of colorectal cancer organoids
Description	Background: Patient derived organoids (PDOs) can be established from colorectal cancers as in vitro models to interrogate cancer biology and its clinical relevance. We applied mass spectrometry (MS) immunopeptidomics to investigate neoantigen presentation and whether this can be augmented through interferon gamma (IFN) or MEK-inhibitors. Methods: Four PDOs from chemotherapy refractory and one from a treatment naïve CRC were expanded to replicates with 100 million cells each, and HLA class I and class II peptide ligands were analysed by MS. Results: We identified an average of 9,936 unique peptides per PDO which compares favourably against published immunopeptidomics studies, suggesting high sensitivity. Loss of heterozygosity of the HLA locus was associated with low peptide diversity in one PDO. Peptides from genes without detectable expression by RNA-sequencing were rarely identified by MS. Only 3 out of 612 non-silent mutations encoded for neoantigens that were detected by MS. Treatment of four PDOs with IFN upregulated HLA class I expression and qualitatively changed the immunopeptidome, with increased presentation of IFN-inducible genes. HLA class II presented peptides increased on average 16-fold with IFN treatment. MEK-inhibitor treatment showed no consistent effect on class I or II HLA expression or the peptidome. Importantly, no additional HLA class I or II presented neoantigens became detectable with any treatment. Conclusions: Only 3 out of 612 non-synonymous mutations encoded for neoantigens that were detectable by MS. Although MS has sensitivity limits and biases, and likely underestimated the true neoantigen burden, this established a lower bound of the percentage of non-silent mutations that encode for presented neoantigens, which may be as low as 0.5%. This could be a reason for the poor responses of non-hypermutated CRCs to immune checkpoint inhibitors. MEK-inhibitors recently failed to improve checkpoint-inhibitor efficacy in CRC and the observed lack of HLA upregulation or improved peptide presentation may explain this.
HostingRepository	PRIDE
AnnounceDate	2019-11-27
AnnouncementXML	Submission_2019-11-27_12:04:47.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michal Bassani-Sternberg
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-27 00:56:10	ID requested
⏵ 1	2019-11-27 12:04:49	announced

Newey A, Griffiths B, Michaux J, Pak HS, Stevenson BJ, Woolston A, Semiannikova M, Spain G, Barber LJ, Matthews N, Rao S, Watkins D, Chau I, Coukos G, Racle J, Gfeller D, Starling N, Cunningham D, Bassani-Sternberg M, Gerlinger M, Immunopeptidomics of colorectal cancer organoids reveals a sparse HLA class I neoantigen landscape and no increase in neoantigens with interferon or MEK-inhibitor treatment. J Immunother Cancer, 7(1):309(2019) [pubmed]

ProteomeXchange project tag: Biology/Disease-Driven Human Proteome Project (B/D-HPP), Human Proteome Project

curator keyword: Biomedical

submitter keyword: colorectal cancer, organoids, immunopeptidomics, mass spectrometry

Michal Bassani-Sternberg
contact affiliation	Department of oncology UNIL CHUV Ludwig Institute for Cancer Research Lausanne
contact email	michal.bassani@chuv.ch
lab head
Michal Bassani-Sternberg
contact affiliation	UNIL/CHUV
contact email	michal.bassani@chuv.ch
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2019/11/PXD014017

PRIDE project URI

• PRIDE
  1. PXD014017
     1. Label: PRIDE project
     2. Name: Immunopeptidomics of colorectal cancer organoids